The Central theme of Research Project 4 (RP4) is to refine the current use of Positron Emission Tomography (PET) in prostate cancer as pharmacodynamic and predictive biomarkers during antiandrogen therapy. During ICMIC-2, we performed molecular imaging (Ml) in more than 100 castrate resistant prostate cancer (CRPC) patients using F-FDHT as a marker of androgen receptor (AR) signaling, and F-FDG as a marker of glycolysis. We observed heterogeneity between lesions, with some lesions exhibiting only F-FDG uptake, some only F-FDHT uptake, and some uptake for both tracers. We also found that the F-FDG uptake, as measured by SUVmax, correlated inversely with prognosis in CRPC. Furthermore, we have also participated in the preclinical and early clinical development of two exciting new, next generation antiandrogens (abiraterone and MDV3100), for which Ml studies appear extremely promising in helping to optimize their use in the clinic. During ICMIC-3, we shall exploit Ml imaging study results, as well as human tissue samples obtained from image-directed biopsy analysis and animal models to better understand the molecular basis for these Ml phenotypes. Our research plan includes the following Specific Aims (SA): SA 1: To link the F-FDG and F-FDHT imaging phenotypes in human prostate cancer with underlying genetic alterations; The hypothesis is that the radiotracers F-FDG and V-FDHT mark genetically and metabolically distinct subgroups of human prostate cancer. A novel genome wide analysis strategy will be used which we have previously applied successfully in breast cancer. SA 2: To develop AR-PET Radioligands as a pharmacodynamic biomarker for optimal dosing of novel AR antagonists; the hypothesis is that AR-directed radiopharmaceuticals can determine saturating doses of AR-antagonists in a preclinical PCamodel, SA 3: To explore V-FDG-PET as an early response biomarker during AR-targeted therapies; the hypothesis is that successful inhibition of androgen receptor activity, alone or - in PTEN deficient cells - In combination with PI3K/mT0R inhibition, results in a decrease in F-FDG-uptake as an early marker of treatment response to next generation antiandrogens. SA 3 will also determine whether V-FDG-PET imaging, performed at multiple time-points during drug therapy, can serve as an early marker of response and resistance to novel AR-antagonists in in-vivo models of human prostate cancer. A unique team of co-leaders enriches the study plan with highly complementary skills, in AR pharmacology, genetic analysis and Ml.